In silico and Experimental Study of Two Hydrazones: The Impact of Positional Isomerism and Metal Complexation on Antibacterial and Antioxidant Activities
Year: 2026
Type: article
Abstract: The geometric disposition of pharmacophoric groups is a critical determinant of drug efficacy and target recognition. This study investigated the influence of structural isomerism on the pharmacological performance of two isomeric hydrazone-based drug candidates, differing in the position of the pyridine nitrogen atom and an ethoxy substituent located at the ortho and para positions of an adjacent benzene ring, together with their Fe³⁺ and La³⁺ coordination complexes. The ligands and their corresponding metal complexes were synthesized and structurally characterized using Fourier-transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy. Density Functional Theory (DFT) calculations at the B3LYP/6-311G(d,p) level, molecular docking, and ADMET modelling were employed to evaluate molecular geometry, pharmacokinetic properties, and binding interactions with Escherichia coli DNA Gyrase (PDB: 6F86) and human Keap1 (PDB: 4L7B). Computational predictions were validated through in vitro antibacterial and antioxidant assays. Spectroscopic characterization identified L1 as the linear isoniazid isomer, exhibiting a lower carbonyl stretching frequency (1645 cm⁻¹) than the kinked nicotinic hydrazide analogue (L2). Molecular docking demonstrated that the linear geometry of L1 enabled deeper penetration into the narrow DNA Gyrase binding pocket, forming a stabilizing dual-lock interaction with Glu50 and Asn46, whereas the bent geometry of L2 induced steric hindrance that reduced binding affinity, highlighting the significant influence of structural isomerism. Experimental antibacterial assays corroborated these findings, with L1 exhibiting superior activity relative to L2 and the reference drug. Although the free ligands displayed moderate antioxidant activity, the Fe³⁺ complex (C1) exhibited the strongest radical-scavenging capacity, significantly outperforming C2 and the uncoordinated ligands. This enhanced activity is attributed to the redox-active iron centre and paramagnetic enolic coordination, as supported by NMR analysis. Overall, the isoniazid scaffold proved pharmacologically superior to the nicotinic hydrazide analogue, while the para-oriented pyridine nitrogen and ethoxy substituent promoted a favourable molecular architecture that enhanced antibacterial efficacy. Furthermore, coordination to Fe³⁺ unlocked superior antioxidant activity, identifying C1 as a promising dual-action therapeutic lead candidate.
Institution: Federal University Lokoja
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7218310643